Background/Purpose:  Patients with primary antiphospholipid syndrome (APS) are at risk for endothelial dysfunction and accelerated atherosclerosis.  In systemic lupus erythematosus (SLE), there is a well-established defect in the function of circulating endothelial progenitors, which leads to an accrual of endothelial damage over time.  This defect has been at least partially attributed to elevated levels of type I interferons (IFNs).  Whether these pathways are important in primary APS is unknown.

Methods:   Peripheral blood mononuclear cells (PBMCs) were isolated from patients with primary APS (n=20-30, depending on the specific experiment) or healthy volunteers.  The function of circulating endothelial progenitors was measured by culturing PBMCs under pro-angiogenic conditions and then quantifying their differentiation into mature endothelial cells (ECs).  APS EC differentiation was tested with freshly-isolated PBMCs from primary APS patients, as well as with control PBMCs cultured in the presence of APS sera.  Using quantitative PCR, the expression of three type I IFN-responsive genes was assessed in PBMCs:  PRKR, IFIT1, and IF144.  Expression levels were compared to age- and gender-matched healthy volunteers, and also to patients with SLE (n=15).  The direct role of antiphospholipid antibodies in promoting endothelial progenitor dysfunction was characterized by injecting purified IgG fractions from APS patients and controls into mice.

Results:   Primary APS was associated with a defect in endothelial progenitor function.  When cultured under pro-angiogenic conditions, APS PBMCs produced fewer mature ECs than controls.  Similarly, treatment of control PBMCs with APS sera impaired differentiation into ECs (as compared to heterologous control sera), implicating circulating factors in the defect.  Interestingly, injection of purified IgG from “triple-positive” APS patients into mice impaired the function of murine endothelial progenitors, arguing that the antiphospholipid antibodies themselves can set the phenotype in motion.  PBMCs from patients with primary APS have upregulated expression of the type I IFN-responsive genes PRKR, IFIT1, and IF144, as compared to healthy controls. The IFN signature of primary APS was similar to that seen in SLE patients, and was most robust in the anti-β₂GPI IgG-positive subpopulation of APS patients.

Conclusion: We describe, for the first time to our knowledge, a type I IFN signature in the PBMC fraction of patients with primary APS.  Paralleling this finding, circulating endothelial progenitors appear to be dysfunctional in primary APS.  Whether the endothelial progenitor defect is attributable to elevated type I IFN synthesis, or possibly direct toxicity from antiphospholipid antibodies, is currently under investigation.  This work has the potential to suggest novel approaches to preventing vascular damage in APS patients, such as anti-IFN drugs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/primary-antiphospholipid-syndrome-is-characterized-by-endothelial-progenitor-dysfunction-and-a-type-i-interferon-signature/